S-adenosyl methionine (SAM-e) is made by the body and is a metabolite present in all living cells. Unlike current psychopharmacologic options for treating depression, SAM-e is an agent that is indigenous to the body, and may offer an alternative option for treatment-resistant Major Depression in children and adolescents. The chemical structure of SAM-e was described as early as 1952 (Cantoni G L. The nature of the active methyl donor formed enzymatically from L-methionine and adenosinetriphosphate. J Am Chem Soc 1952; 74:2942-2943.). It has been in use for decades in Europe, and is a prescription medication in such countries as Italy, Spain, Germany and Russia. (Brown R, Bottiglieri T, Colman C. Stop Depression Now: SAMe 1999:Berkley, N.Y., pg. 5).
The first clinical study of SAM-e's use for depression appears to have been conducted in the 1970s (Agnoli A, Andreoli V, Casacchia M, Cerbo R (1976), Effect of S-adenosyl-L-methionine (SAMe) upon depressive symptoms. J Psychiatr Res 1976; 13:43-54) and since then has been repeatedly studied. Specifically, SAM-e has been found effective for treating major depressive disorder in 13 trials comparing it to placebo, and 19 trials comparing it to tricyclic antidepressants with more than 1,400 patients studied. From 1973 to 1988, 14 double-blind, European studies showed that intravenous and intramuscular preparations of SAM-e were more effective than placebo and comparable to imipramine, amitriptyline and clomipramine for treatment of major depression. Since then, SAM-e has been evaluated for various disorders in more than 75 clinical trials involving over 23,000 people (Janicak P G, Lipinski J, Davis J M et al. (1988), S-adenosylmethionine in depression. A literature review and preliminary report. Ala J Med Sci 1988; 25:306-313; Knowlton L. Investigating SAM-e. Geriatric Times 2001, www.geriatrictimes.com/g010923. html.).
The mechanism for SAM-e's effectiveness in Major Depression is unclear (Silveri M M, Parow A M, Villafuerte R A, Damico K E, Goren J, Stoll A L, Cohen B M, Renshaw P F. S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects Biol Psychiatry 2003; 54:833-9) Yet some propose a mechanism that since SAM-e functions as a precursor to methylation, aminopropylation and transulfuration pathways, it is the most important methyl donor in the brain and is essential for polyamine synthesis. Brain methyl group deficiency has been implicated in depression, and polyamine phosphorylation enhancement of neuronal proteins may be involved in its antidepressant mechanisms (Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr 2002; 76:1151S-7S.; Benelli A, Filaferro M, Bertolini A, Genedani S. Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats. Br J Pharmacol 1999; 127:645-54).
SAM-e has been studied in adults using both IM and oral routes. For example, two multicenter double-blind studies, examined both intramuscular (400 mg) and oral SAM-e (1600 mg) in adults and compared it with 150 mg of imipramine (IMI) in patients with Major Depression. Specifically, one study noted antidepressant effects in a double blind multi-center study in which 147 treated patients were given SAM-e intramuscularly at a dose of 400 mg/d vs. 148 patients treated with 150 mg/d of oral imipramine (IMI) over 4 weeks. A Major Depression diagnosis included a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >/=18. A “response” included a fall in HAMD scores of at least 50% with respect to baseline. SAM-e and IMI did not differ significantly on any efficacy measure. SAM-e and IMI both showed a significant antidepressant response—a HAMD improvement of at least 50%. These data show 400 mg/d of intramuscular SAM-e to be comparable to 150 mg/d of oral IMI in terms of anti-depressive efficacy. In the other study, a total of 143 patients received 1600 mg of oral SAM-e and 138 received IMI for a period of 6 weeks. Therefore, both intramuscular (400 mg) and oral SAM-e (1600 mg) in adults was comparable to 150 mg of imipramine (IMI). SAM-e was better tolerated than IMI in both studies (Delle Chiaie R, Pancheri P, Sapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2002; 76:1172S-6S; Pancheri P, Scapicchio P, Chiaie R D. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002; 5:287-94).
Neurology studies support SAM-e's antidepressant effects. In a double-blind, placebo-controlled, crossover study, using random infusions of 800 mg of SAM-e Electroencephalograms (EEGs), event-related potentials (ERPs) and low-resolution brain electromagnetic tomography identified SAM-e as an antidepressant with effects greater than placebo (Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz G M. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography. Am J Clin Nutr 2002; 76:1162S-71S).
Further, SAM-e appears to have a fairly rapid onset of action. When 195 patients were given 400 mg of intramuscular SAM-e for 15 days, their depressive symptoms showed remission on both day 7 and 15 of treatment with SAM-e (Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi G P. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res 1995; 56:295-7).